Incomplete penetrance of NOD2 C483W mutation underlining Blau syndrome.

BACKGROUND: Blau syndrome (BS) is a rare autoinflammatory disorder with NOD2 gain-of-function mutation and characterized by autoactivation of the NFκB pathway. Classically considered a disease of high penetrance, reports on NOD2 mutations underlining BS with incomplete penetrance is limited. CASE PRESENTATION: The proband is a 9-year-old girl presented with brownish annular infiltrative plaques and symmetric boggy polyarthritis over bilateral wrists and ankles. Her skin biopsy revealed noncaseating granulomas inflammation with multinucleated giant cells. A novel C483W NOD2 mutation was identify in the proband and her asymptomatic father. Functional examinations including autoactivation of the NFκB pathway demonstrated by in vitro HEK293T NOD2 overexpression test as well as intracellular staining of phosphorylated-NFκB in patient's CD11b+ cells were consistent with BS. CONCLUSIONS: We reported a novel C483W NOD2 mutation underlining BS with incomplete penetrance. Moreover, a phosphorylated-NFκB intracellular staining assay of CD11b+ was proposed to assist functional evaluation of NFκB autoactivation in patient with BS.

Physicochemical changes and chemical degradation of gliclazide during twin-screw melt granulation.

Using a miscible model formulation consisting of 80% gliclazide (GLZ) and 20% hydroxypropyl cellulose, we investigate how the twin-screw melt granulation process affects the chemical stability and process-induced physicochemical changes of the drug. No degradation was observed in the conveying section that leads to kneading element. Approximately 1/3 of the GLZ degradant was generated at the kneading section, while the remaining 2/3 was generated in the conveying section post-kneading and during cooling outside the barrel. A strong correlation was observed between the overall degradation and the temperature of the granules at the barrel exit. In the kneading section, the degradant content correlates best with the specific mechanical energy. With higher specific mechanical energies, the size of the GLZ crystals was reduced further, resulting in more surface defects. In the section post-kneading element, GLZ degradation correlates best with the granule temperature measured at the kneading section. This knowledge of drug degradation during twin-screw melt granulation can be used to develop processing strategies to maintain drug stability during and post processing.

Enhancement of Electrical Properties by a Composite FePc/CNT/C Cathode in a Bio-Electro-Fenton Microbial Fuel Cell System.

This study focused on an iron phthalocyanine compound with aligned CNTs on the surface of a carbon felt electrode (FePc/CNT/C) to enhance the bio-electro-Fenton microbial fuel cell system cathodes reaction rate of hydrogen peroxide and the electrical plate. Experiments of polarization curves and power density, decolorization of Reactive Black 5 (RB5), and scanning electron microscopy (SEM) measured the characteristics of the cathode plate. FePc/CNT/C presented better electrical properties (open-circuit voltage, maximum current density, and maximum power density) than that of CNT/C and C, as FePc is a catalyst and its planar structure could easily adhere to CNT to enhance the reduction reaction at the cathode and provide higher specific surface area. The optimal decolorization of RB5 dye, as achieved with the FePc/CNT/C electrode, was 61.79% among the three cathode electrodes in the bio-electro-Fenton microbial fuel cell system, and the maximum number of hydroxyl radicals was generated for the cathode electrode of FePc/CNT/C. These results suggest that the bio-electro-Fenton microbial fuel cell system could be applied as an energy-saving and efficient approach for dye-containing wastewater treatment.

Interfacial bonding in formulated bilayer tablets.

To take full advantage of the drug delivery benefits offered by bilayer tablets, the common issue of weak interfacial bonding strength (IBS) with manufacturing must be overcome. This work seeks to characterize the effects of composition in individual layers and compaction pressure on the IBS. Mixtures of MCC and lactose in different ratios with and without HPMC were used where the first layer was compacted with two different pressures (20 and 100 MPa) followed by a second layer compaction pressure of 200 MPa. After identifying the failure mode as either at the interface or within a layer, the complex trends of bilayer tablet IBS as a function of MCC content were explained by considering the interplay between particle bonding strength and bonding area at the interface.

Minimum Interfacial Bonding Strength for Bilayer Tablets Determined Using a Survival Test.

PURPOSE: To identify the minimum interfacial bonding strength (IBS) required for bilayer tablets to sustain the stresses experienced during manufacturing, transportation, and handling. METHODS: Bilayer tablets of a number of formulations with systematically varied IBS were prepared on a materials testing macine. Five bilayer tablets with the same IBS were repeatedly dropped at a fixed height in a friabilator and integrity of the interface was periodically examined. The number of tablets free from observable defects at the interface was plotted as a function of the number of drops. The IBS for all five tablets to remain intact after 1000 drops was taken as the minimum IBS for a given formulation. RESULTS: The minimum IBS depends on both layer composition and tablet size. For bilayer tablets made with more brittle materials or a larger size, a higher minimum IBS is required to pass the survival test. The incorporation of HPMC leads to a lower minimum IBS. An IBS of 0.26 MPa is sufficient for all bilayer tablet formulations and sizes to pass the survival test in this work. CONCLUSIONS: A minimum IBS of 0.26 MPa is recommended as a tentative criterion for bilayer tablets of most materials to avoid quality issues arising from inadequate IBS.

Relationship between hydrate stability and accuracy of true density measured by helium pycnometry.

Mechanical properties of a material, such as hardness and elastic modulus, depend on porosity exponentially. Thus, an accurate characterization of material mechanical properties requires correct porosity, which depends on the accuracy of measured true density. Helium pycnometry is the most common technique for determining true density of a powder material but it is not suitable for materials containing volatile components. For unstable hydrates, dehydration during measurement releases water and invalidates the ideal gas law used for calculating sample volume. Consequently, measured true density is over-estimated, which causes gross errors in mechanical properties extrapolated to zero porosity. This work shows that physical stability and the dehydration kinetics, determined by both water-bonding structures and bonding energy, directly affect the magnitude of error in measured true density.

Comparative analyses of flow and compaction properties of diverse mannitol and lactose grades.

Appropriate selection of excipient grade during tablet formulation development depends on thorough knowledge in their compaction and flow properties. Each chemically unique pharmaceutical excipient is usually available in several commercial grades that are widely different in powder properties, which influence their performance for a specific formulation application. In this work, 11 grades of mannitol were systematically characterized, in terms of their particulate, flow and tableting properties, and compared against 5 grades of lactose. Principal component analysis (PCA) identified significant correlations among selected variables, such as particle size, surface area, flowability, wall friction, plasticity parameter, tensile strength, and tablet brittleness. PCA also revealed similar grades of the two excipients, which may be used to select replacement grade, if needed, based on similarity in their overall properties.

Superior Plasticity and Tabletability of Theophylline Monohydrate.

A theophylline monohydrate (THm) powder, with particle size and shape substantially similar to a theophylline anhydrate powder, was prepared by vapor-mediated phase conversion. The elimination of possible contributions by particle size and shape to tableting properties made it possible to unambiguously identify the role of bonding area and bonding strength on powder tableting performance. It was also shown that accurate true density is essential for correct analysis and understanding of tableting behavior of THm. Experimental evidence revealed surprisingly high plasticity of THm. This is explained by its unique ladder-like structure, where rigid molecular dimers (rungs) weakly connect to more rigid water chains (rails). The low energy barrier for moving rigid dimers down the rigid water chains enables facile propagation of dislocations in THm crystals when subjected to an external stress.

Tensile and shear methods for measuring strength of bilayer tablets.

Both shear and tensile measurement methods have been used to quantify interfacial bonding strength of bilayer tablets. The shear method is more convenient to perform, but reproducible strength data requires careful control of the placement of tablet and contact point for shear force application. Moreover, data obtained from the shear method depend on the orientation of the bilayer tablet. Although more time-consuming to perform, the tensile method yields data that are straightforward to interpret. Thus, the tensile method is preferred in fundamental bilayer tableting research to minimize ambiguity in data interpretation. Using both shear and tensile methods, we measured the mechanical strength of bilayer tablets made of several different layer combinations of lactose and microcrystalline cellulose. We observed a good correlation between strength obtained by the tensile method and carefully conducted shear method. This suggests that the shear method may be used for routine quality test of bilayer tablets during manufacturing because of its speed and convenience, provided a protocol for careful control of the placement of the tablet interface, tablet orientation, and blade is implemented.

A critical Examination of the Phenomenon of Bonding Area - Bonding Strength Interplay in Powder Tableting.

PURPOSE: Although the bonding area (BA) and bonding strength (BS) interplay is used to explain complex tableting behaviors, it has never been experimentally proven. The purpose of this study is to unambiguously establish the distinct contributions of each by decoupling the contributions from BA and BS. METHODS: To modulate BA, a Soluplus® powder was compressed into tablets at different temperatures and then broken following equilibration at 25°C. To modulate BS, tablets were equilibrated at different temperatures. To simultaneously modulate BA and BS, both powder compression and tablet breaking test were carried out at different temperatures. RESULTS: Lower tablet tensile strength is observed when the powder is compressed at a lower temperature but broken at 25°C. This is consistent with the increased resistance to polymer deformation at lower temperatures. When equilibrated at different temperatures, the tensile strength of tablets prepared under identical conditions increases with decreasing storage temperature, indicating that BS is higher at a lower temperature. When powder compression and tablet breaking are carried out at the same temperature, the profile with a maximum tensile strength at 4°C is observed due to the BA-BS interplay. CONCLUSION: By systematically varying temperature during tablet compression and breaking, we have experimentally demonstrated the phenomenon of BA-BS interplay in tableting.

Dependence of tablet brittleness on tensile strength and porosity.

An analysis of data collected from 25 sets of diverse pharmaceutical powders has identified that an exponential growth function satisfactorily describes the relationship between tablet brittleness and tablet porosity while a power law function well describes the relationship between tablet brittleness and tensile strength. These equations have the potential to facilitate better characterization of tablet mechanical properties and to guide the design and optimization of pharmaceutical tablet products.

Outcome of patients with positive heparin-platelet factor-4 antibodies: A retrospective multi-institutional observational study.

Studies show increased mortality with positive heparin-platelet factor-4 (H-PF4) antibodies, especially in hemodialysis patients. We aimed to compare mortality and thrombosis in hospitalized patients with positive, equivocal and negative H-PF4 antibody results. Information was collected on these patients using a multi-institutional retrospective electronic medical record review. Patients tested for H-PF4 antibodies by commercial ELISA during the years 2006 to 2010 were identified. We compared 30-day, 90-day and 1-year mortality in patients with negative, equivocal and positive H-PF4 test and evaluated the relationship between H-PF4 status and rate of thrombosis. Four hundred and seventeen patients had ELISA testing for H-PF4 antibodies. Forty-four patients had equivocal (optical density value 0.4-0.9) and 21 had positive (value 1) H-PF4 antibody test. There were no statistically significant differences in mortality between patients with negative, equivocal and positive results at all three time points (p = 0.22, 0.27 and 0.38, respectively) even after excluding patients with thrombosis (p = 0.22, 0.24 and 0.31, respectively). Age and Charlson score were associated with increased 30-day, 90-day and 1 year mortality. Odds ratio of having thrombosis was 23.1 for positive vs. equivocal results (p < 0.001); however, there was no statistically significant difference between equivocal vs. negative results (p = 0.22). Our results revealed no association between H-PF4 status and mortality, as well as no difference in 1-year survival between the positive and negative groups.